1. Field of the Invention
The invention relates to a process for the preparation of benzaldehydes which carry an electron-withdrawing substituent in a least one of the ortho- and para-positions.
Such benzaldehydes are important in the preparation of pharmaceutically active preparations, for example, 1,4-dihydropyridine derivatives are prepared from o-nitrobenzaldehyde (DE-OS (German Published Specification) 1,670,827).
2. Description of the Related Art
As the usual classical aldehyde syntheses fail in the synthesis of aldehydes having electron-withdrawing substituents, for example in the synthesis of o-nitrobenzaldehyde, an extensive patent literature about special processes exists to this day. Some of the processes claimed relate in the first step to the side chain halogenation of the underlying o-nitrotoluene with subsequent hydrolysis (DE-OS (German Published Specification) 2,842,360) or oxidation (DE-OS (German Published Specification) 2,708,115), DE-OS (German Published Specification) 2,948,058). However, nuclear halogenation products are always also formed in the side chain halogenation so that complicated purification steps are necessary to obtain o-nitrobenzaldehyde in pharmaceutical quality.
The direct oxidation of o-nitrotoluene using chromium(VI) oxide is problematical because of waste water pollution. With the use of other oxidizing agents, such as cerium(IV) perchlorate (EP 205,173) or cobalt(III) sulphate, the high dilution of the reaction mixture required and the low conversions attainable speak against its realisation as an economical process.
Even in the oxidation of o-nitro-styrene using oxygen in the presence of various catalyst, only low conversions are achieved (DE-OS (German Published Specification) 2,805,402), while the somewhat more complicated use of ozone at -20.degree. C. gives better yields (DE-OS (German Published Specification) 2,829,346). However, the preparation of o-nitro-styrene is troublesome and in turn contains a less desirable halogenation step.
Other processes have therefore been developed for the oxidative degradation of compounds which can be prepared by C-C coupling, starting from inexpensive o-nitrotoluene. The oxidation of 2-nitrophenylpyruvic acid with potassium permanganate (DE-OS (German Published Specification) 2,415,061) or with hypochlorite and subsequent hydrolysis (DE-OS (German Published Specification) 2,415,062) gives yields of only 27 or 36%. The reaction of hydrogen peroxide with 2-nitrophenylpyruvic acid derivatives (EP-92,267) gives 39 to about 50% of o-nitrobenzaldehyde, in each case starting from o-nitrotoluene.
The oxidation of .beta.-dimethylamino-2-nitrostyrene using sodium hypochlorite or using 30% strength hydrogen peroxide has also already been described (JP 60-25,957 (1985)). To this end, 2-nitrotoluene was initially used as a starting material and was reacted with the orthoamide dimethylformamide dimethyl acetal to give .beta.-dimethylamino-2-nitrostyrene. As the described oxidation to the aldehyde is carried out in acetonitrile-water mixtures, dimethylformamide and unreacted o-nitrotoluene must be removed by distillation, which, because of the instability of the nitro-styrenes, is not without risk. The yield when using 30% strength hydrogen peroxide is 55% or 42.5%, relative to the expensive dimethylformamide acetal. When using hypochlorite and then hydrolysing, 68 or 53% of the theoretical yield is obtained. Reworking showed that the yield can be increased to up to 80% of the theoretical yield when using 70% strength hydrogen peroxide; however, the use of highly concentrated hydrogen peroxide is problematical.
In principle, the oxidation of enamines with oxygen is also known (Tetrah. Letters 1968, 3271 and 1968, 3267; U.S. Pat. No. 3,661,942), but the preparation of aldehydes by this method has been described as unselective. The oxidation of heterocyclic enamines with O.sub.2 in the presence, for example, of 2-.beta.-amino-vinyl-5-nitro-imidazole to give 5-nitro-imidazole-2-carbaldehyde, has been described as not possible (Ann. 1975, 1465).